Reparative and recovery mechanisms following tissue damage occur with variable effectiveness in patients with white matter disorders across different disease stages. This might explain why a mismatch between clinical and magnetic resonance imaging (MRI) findings is often found in these patients. Among the mechanisms of recovery, brain functional plasticityPlasticity is likely to be one of the most important with several possible different substrates (including increased axonal expression of sodium channels, synaptic changes, increased recruitment of parallel existing pathways or “latent” connections, and reorganization of whole-brain functional networks). The application of fMRI has shown that functional cortical changes do occur after white matter injury of different etiology, that such changes are related to the extent of structural damage, and that they can contribute in limiting the clinical consequences of central nervous system damage. Conversely, the failure or exhaustion of the adaptive properties of the cerebral cortex might be among the factors responsible for the accumulation of irreversible neurological deficits in patients with white matter disorders.